A novel BMP-2–loaded hydroxyapatite/beta-tricalcium phosphate microsphere/hydrogel composite for bone regeneration

Abstract

Although bone morphogenetic protein (BMP) has potent osteoinductivity, the potential adverse events attributed to its burst release prevent its widespread clinical application. Therefore, there is a strong need for BMP delivery systems that maximize osteoinductivity while preventing adverse effects. We evaluated the bone-regenerating potential of NOVOSIS putty (NP), a novel composite combining hydroxyapatite, beta-tricalcium phosphate microsphere/poloxamer 407-based hydrogel, and recombinant human (rh) BMP-2. In vitro assessment of release kinetics by enzyme-linked immunosorbent assay demonstrated sustained release of rhBMP-2 from NP and burst release from collagen sponge (CS), and in vivo assessment of release kinetics by longitudinal tracking of fluorescently labeled rhBMP-2 showed a longer biological half-life of rhBMP-2 with NP than with CS. Furthermore, osteogenic gene expression in MC3T3-E1 cells was significantly higher after co-culture with NP than after co-culture with CS, suggesting that the sustained release of rhBMP-2 from NP effectively contributed to the differentiation of osteoblasts. In a rat spinal fusion model, the volume and quality of newly formed bone was higher in the NP group than in the CS group. Use of NP results in efficient bone regeneration through sustained release of rhBMP-2 and improves the quality of BMP-induced bone.

Advances in bone regeneration with growth factors for spinal fusion: A literature review

“…Burst release of BMPs induces a strong osteogenic effect at the graft site, allowing for early bone regeneration. However, rapidly released BMPs cause bone formation not only at the target site but also in the surrounding area (ectopic ossification at unintended sites), resulting in poor quality new bone with abundant fatty marrow in the central region [ 60 , 61 ]. In addition, burst release is more likely to produce side effects such as concentration-dependent inflammatory reactions [ 54 , 62 ].…”

“…In contrast, sustained release of BMPs attenuates the spread of the inflammatory response to the surroundings in the early stages of the bone formation process, resulting in the induction of new bone that does not differ substantially from the size of target sites [ 62 , 63 ]. In addition, long-term release of BMPs can lead to the formation of a substantial amount of new bone in the center of the grafted site [61] . However, sustained release takes a longer time to achieve adequate bone formation.…”

“…While these have good biocompatibility and biodegradability, they present drawbacks such as mechanical weakness and immunogenicity [59] . Mechanically weak collagen sponges are easily compressed by the surrounding tissue and cause rapid leakage of the rhBMP-2 solution [64] , such that approximately 60–80% of BMP-2 is released after only 1 day of implantation [ 61 , 63 ], and only approximately 5% of rhBMP-2 remains in vivo , 2 weeks after implantation [ 65 , 66 ].…”

“…We have developed NOVOSIS putty®, a novel ceramic/polymer composite that combines HA granules, β-TCP microspheres, and poloxamer 407-based hydrogel (HA/β-TCP microsphere/poloxamer 407 hydrogel) [ 61 , 62 ]. HA/β-TCP microsphere/poloxamer 407 hydrogel is an exceptional handling composite with injectable and moldable properties and exhibits improved sustained release of rhBMP-2 than the collagen sponge.…”

Concentration-Dependent Efficacy of Recombinant Human Bone Morphogenetic Protein-2 Using a HA/β-TCP Hydrogel Carrier in a Mini-Pig Vertebral Oblique Lateral Interbody Fusion Model

“…Therefore, we have investigated the use of a carrier that provides sustained release of BMP-2 to overcome this drawback. In addition, this carrier is easy to handle and has other desirable properties [15,16,22,23], including good mechanical strength and spatial control of new bone formation [24][25][26][27]. The carrier under discussion is a system based on a ceramic/polymer composite material that has received particular attention as a sustained-release BMP-delivery system.…”